The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disr...The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.展开更多
HIV-1整合酶是HIV-1生命周期中必不可少的酶之一,已成为目前最具潜力的抗HIV药物设计的靶点之一。2007年,Merk公司研发的MK-5108作为首个整合酶抑制剂药物被美国食品药物管理局批准上市,标志着整合酶抑制剂研究的重大突破,也激发了抗HI...HIV-1整合酶是HIV-1生命周期中必不可少的酶之一,已成为目前最具潜力的抗HIV药物设计的靶点之一。2007年,Merk公司研发的MK-5108作为首个整合酶抑制剂药物被美国食品药物管理局批准上市,标志着整合酶抑制剂研究的重大突破,也激发了抗HIV-1整合酶抑制剂研究的新一轮高潮。计算机辅助药物设计(computer-aided drug design,CADD)具有效率高、成本低等特点,基于计算机辅助手段合理药物设计已取得了很大的进展。文章综述了近几年来计算机辅助设计抗HIV整合酶抑制剂及耐药机理方面的研究进展。展开更多
Two new compounds, linderafurane A and linchuniinone, were isolated from the root of Lindera chunii Merr.. The structures were elucidated by spectroscopic methods, and their activities against HIV-1 integrase were eva...Two new compounds, linderafurane A and linchuniinone, were isolated from the root of Lindera chunii Merr.. The structures were elucidated by spectroscopic methods, and their activities against HIV-1 integrase were evaluated.展开更多
The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 1...The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 19.434（5） A, β = 104.411（4）°, Mr = 804.85, Dc = 1.288 g/cm3, V = 4149.2（17） A3, Z = 4, F（000） = 1696, #（MoKa） = 0.089 mm-1T = 296（2） K, 7279 independent reflections with 3172 observed ones （I 〉 2δ（/））, R = 0.0520 and wR = 0.1203 with GOF = 0.928 （R = 0.1464 and wR = 0.1657 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O-H…O hydrogen bonds. Preliminary bioassays indicated that the title compound has a potent inhibitory activity against the strand transfer process of HIV-1 integrase.展开更多
Twenty novel furanone derivatives, based on the structure of raltegravir which was the first HIV-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synth...Twenty novel furanone derivatives, based on the structure of raltegravir which was the first HIV-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synthesized and characterized by ^1H NMR, IR and MS. The biological activities of these compounds against HIV-1 IN in vitro were evaluated. The assay results indicate that the replacement of pyrimidinone with furanone decreased the inhibitory activity of the compounds to HIV-1 IN. Compounds 3i, 3j and 3t show moderate inhibitory activity against HIV-1 IN and selectively inhibit the strand transfer reaction.展开更多
Integrase（IN） plays an essential role in the process of HIV-1 replication.IN inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular...Integrase（IN） plays an essential role in the process of HIV-1 replication.IN inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular Similarity Induces Analysis（CoMSIA） methods.A set of 42 compounds were randomly selected as the training set（35） and test set（7）.Firstly,a good pharmacophore（goodness of hit=0.787） was obtained and used to align ligands.Then,predictive models were constructed with the CoMFA and CoMSIA methods based on the pharmacophore alignment.As a result,the CoMS1A method yielded the best model with an r2 of 0.955 and a q2 of 0.665,which can predict the activities of the tested DKAs very well（r2=0.559）.Finally,DKAs were docked into IN,and the predicit modes were superimposed on the contour maps obtained from the best CoMSIA model.The superimposed maps gave a visualized and meaningful insight into the inhibitory behaviors,providing significantly useful information for the rational drug design of anti-IN agents.展开更多
基金supported by the National Natural Science Foundation of China (No. 30472166)the Tianjin Commission of Science and Technology (06YFGZSH07000)
文摘The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.
文摘HIV-1整合酶是HIV-1生命周期中必不可少的酶之一,已成为目前最具潜力的抗HIV药物设计的靶点之一。2007年,Merk公司研发的MK-5108作为首个整合酶抑制剂药物被美国食品药物管理局批准上市,标志着整合酶抑制剂研究的重大突破,也激发了抗HIV-1整合酶抑制剂研究的新一轮高潮。计算机辅助药物设计(computer-aided drug design,CADD)具有效率高、成本低等特点,基于计算机辅助手段合理药物设计已取得了很大的进展。文章综述了近几年来计算机辅助设计抗HIV整合酶抑制剂及耐药机理方面的研究进展。
基金supported by grants from The National Natural Science Foundation of China(10974008)"973" Program(2009CB930200)+2 种基金Beijing Natural Science Foundation(5072002 and 7082006)Research Fund for the Doctorate Program of Higher Education of China(200800050003)Research Fund for the Doctorate Program(X0015001200801)~~
文摘Two new compounds, linderafurane A and linchuniinone, were isolated from the root of Lindera chunii Merr.. The structures were elucidated by spectroscopic methods, and their activities against HIV-1 integrase were evaluated.
基金supported by the National Natural Science Foundation of China(No.21102003)National Students'Innovation and Entrepreneurship Training Program(No.201210361094)Scientific Research Foundation for the Introduction of Talent and Young Teachers Scientific Research Foundation of Anhui University of Science&Technology(11214,2012QNY27)
文摘The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 19.434（5） A, β = 104.411（4）°, Mr = 804.85, Dc = 1.288 g/cm3, V = 4149.2（17） A3, Z = 4, F（000） = 1696, #（MoKa） = 0.089 mm-1T = 296（2） K, 7279 independent reflections with 3172 observed ones （I 〉 2δ（/））, R = 0.0520 and wR = 0.1203 with GOF = 0.928 （R = 0.1464 and wR = 0.1657 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O-H…O hydrogen bonds. Preliminary bioassays indicated that the title compound has a potent inhibitory activity against the strand transfer process of HIV-1 integrase.
基金Supported by the National Natural Science Foundation of China(No.20872082)the Natural Science Foundation of Shandong Province,China(No.Y2007C060)
文摘Twenty novel furanone derivatives, based on the structure of raltegravir which was the first HIV-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synthesized and characterized by ^1H NMR, IR and MS. The biological activities of these compounds against HIV-1 IN in vitro were evaluated. The assay results indicate that the replacement of pyrimidinone with furanone decreased the inhibitory activity of the compounds to HIV-1 IN. Compounds 3i, 3j and 3t show moderate inhibitory activity against HIV-1 IN and selectively inhibit the strand transfer reaction.
基金Supported by the National Natural Science Foundation of China（Nos.31100523,31171267,21173014） and the Beijing Outstanding Personnel Training Foundation,China（No.2012D005015000006）.
文摘Integrase（IN） plays an essential role in the process of HIV-1 replication.IN inhibitors of diketo acid derivatives（DKAs） were analysed by the Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular Similarity Induces Analysis（CoMSIA） methods.A set of 42 compounds were randomly selected as the training set（35） and test set（7）.Firstly,a good pharmacophore（goodness of hit=0.787） was obtained and used to align ligands.Then,predictive models were constructed with the CoMFA and CoMSIA methods based on the pharmacophore alignment.As a result,the CoMS1A method yielded the best model with an r2 of 0.955 and a q2 of 0.665,which can predict the activities of the tested DKAs very well（r2=0.559）.Finally,DKAs were docked into IN,and the predicit modes were superimposed on the contour maps obtained from the best CoMSIA model.The superimposed maps gave a visualized and meaningful insight into the inhibitory behaviors,providing significantly useful information for the rational drug design of anti-IN agents.
